Borrelia B-cell Diagnostics

Lyme Disease Clinical Trial

— BRILLIANT  

Official title:

Extensive Investigation of Immune Responses Against Borrelia Burgdorferi to Improve Diagnosis of Lyme Disease in Children: an Observational Study (BRILLIANT Study)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06045416
• Other study ID #: 2023-00528
• Status: Recruiting
• Start date: April 2, 2024
• Est. completion date: November 1, 2028

Study information

• Verified date: December 2023
• Source: University Children's Hospital, Zurich
• Contact: Patrick M Meyer Sauteur, MD PhD
• Phone: 0041 44 266 78 96
• Email: patrick.meyersauteur[@]kispi.uzh.ch
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

The investigators propose a single center, prospective observational study in children with Lyme disease (LD), the Borrelia B-cell diagnostics (BRILLIANT) study, to assess the immune response against Borrelia burgdorferi (Bb) with the following main objectives:

1. Development of Bb-specific ASC ELISpot as a new test method for diagnosis of early LD.

There is an urgent unmet clinical need for a better diagnostic tool for early LD, as the current standard two-tier testing has low sensitivity in recently infected patients and may show false positive results in recovered patients due to long-term persistence of antibodies against Bb. The measurement of Bb-specific ASC with the ELISpot assay my has the potential to overcome these issues and to improve diagnosis in early LD.

2. Extensive analysis of the immune response in LD. The immune response in LD is not well understood. Large-scale studies assessing the detailed immune cell subsets/phenotypes present in blood, CSF, or synovial fluid of LD patients with respective manifestations are lacking.

3. Isolation and characterization of causative Bb species. Existing literature suggests that Bb genospecies and/or genotypes may determine virulence and manifestations, but large-scale studies assessing Bb genospecies/genotypes in different manifestation of LD are lacking.

4. Collection of clinical data about symptoms, severity, routine laboratory and diagnostic test results, treatment, and outcome of LD.

5. Biobanking samples for analysis in the future.

Project population

Inclusion criteria: Children, 0-17 years of age, at University Children's Hospital Zurich:

• LD differential diagnosis cohort: Patients presenting at the ED with differential diagnosis of LD according to the treating physician.

• Control cohort: Previously healthy patients (HC) with routine blood investigations presenting at the ED or PID outpatient department

Exclusion criteria: Primary or secondary immunodeficiency.

Description:

Background:

Lyme disease (LD) is the most common tick born disease in Europe. It is caused by an infection with several genospecies of the spirochaetal bacteria Borrelia burgdorferi (Bb).

Although classical disease manifestations are well-known, the clinical presentation in children is often variable and inconclusive, which results in delayed diagnosis and treatment.

Methods/design:

The investigators are conducting an observational cohort study in children with LD. Study site is the University Children's Hospital Zurich. 502 patients will be enrolled. Children from 0-17 years of age presenting with signs and symptoms suspicious for LD are included in the study. Previously healthy children with routine blood investigation are enrolled as healthy controls. Patients will be excluded in cases of primary or secondary immunodeficiency.

Clinical and routine laboratory data regarding course and outcome, as well as venous blood samples are collected at first hospital contact and follow up visits (FUP). FUPs are scheduled at 28 days, 3 months and 6 months after hospital admission. Cerebrospinal fluid (CSF) and synovial fluid (SF) will be collected for the study only if sampling is indicated due to diagnostic or therapeutic reasons.

Primary objectives are to assess Bb-specific ASCs in blood using ELISpot assay, in order to develop new diagnostic tool for early LD. In addition, the investigators will examine immune response in patients with various LD manifestations using flow cytometry, ELISA assay, and ELISpot assay. Finally, the investigators will perform whole genome sequencing of causative Bb-species isolated from patients to investigate potential differences in virulence and associations with clinical presentations.

Discussion:

This single-centre, observational cohort study will improve the understanding of immunological response in LD in children. It will also provide new information about the virulence of distinct LD causing Bb-genospecies and will test a new approach in the diagnosis of early LD.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 502
• Est. completion date: November 1, 2028
• Est. primary completion date: November 1, 2026
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 1 Month to 17 Years

Eligibility

Inclusion Criteria:

• Patients presenting at the ED with differential diagnosis of LD according to the treating physician

Exclusion Criteria:

• Patients will be excluded in cases of primary or secondary immunodeficiency

Related Conditions & MeSH terms

• Lyme Disease

Intervention

Procedure:
• venous blood puncture
Venous blood puncture performed at first hospital contact, and at 28 days, 3 month, and 6 months after hospital admission. Lumbar puncture and joint puncture for the study will be performed if it is indicated due to diagnostic or therapeutic reasons.

Locations

Country	Name	City	State
Switzerland	Chidren's Hospital Zurich	Zürich

Sponsors (2)

Lead Sponsor	Collaborator
University Children's Hospital, Zurich	Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland

Country where clinical trial is conducted

Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Bb-specific ASCs per 10^6 PBMCs	Method: Quantification of Bb-specific ASCs (IgM, IgG, IgA) per 10^6 PBMCs using ELISpot assay; Time: 0 d (hospital admission), (1-14 d), 28 d, 3 m, and 6 m (after hospital admission)	10/2023 - 10/2026
Secondary	Measurement of percentage and median fluorescence intensity (MFI) of immune cell subsets in blood, CSF and SF	Method: Measuring percentage and MFI of innate and adaptive immune cell subsets using established panels for flow cytometry; innate immune cells: DC, GC, Nk-cells; adaptive immune cells: Tc-cells and Th-cell subsets (Th1, Th2, Th17, Treg), B-cells; Time: 0 d (hospital admission), (1-14 d), 28 d, 3 m, and 6 m (after hospital admission)	10/2023 - 10/2028
Secondary	Concentration of serum antibody levels (IU/mL)	Method: Measuring total serum IgM, IgG, IgA antibody levels using Enzyme-linked immunosorbant assay (ELISA); Time: 0 d (hospital admission), (1-14 d), 28 d, 3 m, and 6 m (after hospital admission)	10/2023 - 10/2028
Secondary	Number of Bb-specific T cells per 10^6 PBMCs	Method: Quantification of Bb-specific INF-gamma-secreting T cells per 10^6 PBMCs using INF-gamma ELISpot assay.; Time: 0 d (hospital admission), (1-14 d), 28 d, 3 m, and 6 m (after hospital admission)	10/2023 - 10/2028
Secondary	Concentration of plasma and CSF cytokine/chemokine levels (pg/mL)	Method: Analysis of plasma and CSF cytokine/chemokine profiles using Multiplex Bead Array Kits; pro-inflammatory cytokines: interferon gamma (IFN-?), Tumor necrosis factor A (TNF-a), IL-1, IL-17, IL-6 and IL-8; anti-inflammatory cytokines: IL-10 and IL-13; chemokines: Stromal cell-derived factor 1 (CXCL12), B cell-attracting chemokine 1 (CXCL13), IFN-? inducible protein (IP-10/CXCL-10); Time: 0 d (hospital admission), (1-14 d), 28 d, 3 m, and 6 m (after hospital admission)	10/2023 - 10/2028
Secondary	Portion of Bb positive LD patients by culture/PCR, identification of Bb species in LD patients	Method: Bb culture and PCR out of blood, CSF and SF samples; Identification of Bb genospecies using PCR and whole genome sequencing (WGS); - Expected Bb genospecies: Bb sensu stricto, B. garinii, B. afzelii, B. spielmanii, B. mayonii; Time: 0 d (hospital admission), (1-14 d), 28 d, 3 m, and 6 m (after hospital admission)	10/2023 - 10/2028